RANBP2 – Familial Acute Necrotizing Encephalopathy

Familial acute necrotizing encephalopathy (ANE1) is a rare, rapidly progressive encephalopathy triggered by common viral infections and characterized by fever (HP:0001945), seizures (HP:0001250) and rapid coma. While most ANE cases are sporadic, an autosomal dominant form (ANE1) with incomplete penetrance is caused by heterozygous variants in RANBP2 (PMID:21945312). Molecular diagnosis of ANE1 enables early intervention and informs family screening.

Inheritance of ANE1 is autosomal dominant with incomplete penetrance. To date, four unrelated probands harboring RANBP2 variants have been reported: the first Italian child with a recurrent episode carrying the missense c.1754C>T (p.Thr585Met) in RANBP2 (PMID:21945312), a 9-year-old Caucasian female and her mother both with c.1754C>T (p.Thr585Met) (PMID:19811512), two atypical female patients with c.1754C>T (p.Thr585Met) (PMID:25522933), and a child with homozygous c.1966A>G (p.Ile656Val) variant suggesting increased penetrance (PMID:36029610).

Segregation analysis supports pathogenicity: in one kindred, both the mother and daughter with recurrent ANE episodes carry the c.1754C>T (p.Thr585Met) variant, with an affected relative count of 1 (PMID:19811512).

The variant spectrum in ANE1 is dominated by the recurrent missense c.1754C>T (p.Thr585Met) identified across multiple families, alongside rare stopgain variants such as c.467C>G (p.Ser156Ter) (PMID:21945312) and homozygous missense alleles like c.1966A>G (p.Ile656Val) (PMID:36029610). No founder alleles or deep-intronic variants have been reported.

Functional assays demonstrate that ANE1-linked RANBP2 mutations impair critical Nup358 interactions. The common p.Thr585Met variant reduces binding to GW182/TNRC6A and compromises miRNA-mediated silencing (PMID:33962210), diminishes Argonaute sumoylation and IL6 mRNA repression (PMID:33600493), and attenuates COX11 interaction suggestive of mitochondrial dysfunction (PMID:34400285). These data align with a haploinsufficiency or dominant-negative mechanism.

No studies to date have refuted the RANBP2–ANE1 association; clinical presentations and neuroradiological findings are consistent across reports, and immunomodulatory therapy has been employed empirically (PMID:21945312).

Integration of genetic and functional evidence supports a Moderate ClinGen classification: multiple unrelated probands, one multi-generational segregation event, and concordant in vitro functional data. Further natural history studies and animal models could strengthen the evidence base.

Key take-home: Heterozygous RANBP2 c.1754C>T (p.Thr585Met) and related variants cause autosomal dominant ANE1; genetic testing informs diagnosis, family counseling, and early supportive care.

References

• Brain & development • 2012 • Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful? PMID:21945312
• Developmental medicine and child neurology • 2010 • Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. PMID:19811512
• Clinical neurology and neurosurgery • 2022 • First case with RANBP2 biallelic mutation and severe acute necrotizing encephalopathy phenotype. PMID:36029610
• European journal of paediatric neurology • 2015 • RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype. PMID:25522933
• Biochemical and biophysical research communications • 2021 • Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA function. PMID:33962210
• PLoS genetics • 2021 • RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes. PMID:33600493
• Neuroscience letters • 2021 • RANBP2 mutation causing autosomal dominant acute necrotizing encephalopathy attenuates its interaction with COX11. PMID:34400285

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